Myotonic Dystrophy is the most prevalent adult onset muscular dystrophy. The pathology of Myotonic Dystrophy (DM) is driven by a poly-CTG expansion in the 3'- untranslatated region of the DMPK gene. Once translated, the DMPK transcript retained in nuclear foci, and the resulting RNA/protein (RNP) complex sequesters muscleblind proteins as well as general transcription factors. Small molecules that sequence- specifically target poly-CUG motifs and disrupt protein-RNA interactions have the potential to inhibit all the aforementioned RNA/protein interactions and treat the root of DM, providing lifelong disease remission. Therefore, the broad, long-term objective of this project is the development of cyclic peptide mimics that sequence-specifically target poly-CUG motifs and disrupt protein/RNA interactions. To achieve this objective, our Specific Aims are: 1) to identify cyclic peptide scaffolds that sequence-specifically bind poly-CUG RNA oligonucleotides by screening cysteine-constrained phage libraries against a poly-CUG RNA target. 2) To synthesize the cysteine-constrained peptides that we identify and biophysically characterize their RNA binding properties. 3) To conduct analog synthesis to identify mimics for the disulfide macrocyclic linkage that maintain RNA-binding properties and enhance stability. Once cyclic peptide mimics have been identified, future collaborative efforts will be directed toward assessing the in vivo potential of each compound toward disrupting the inclusion of the DMPK transcript in nuclear foci, disrupting the interaction of muscleblind proteins with the DMPK/RNP complex, and disrupting the interaction between the RNP complex and general transcription factors. to public health: All current approaches to treating Myotonic Dystrophy rely upon symptom management. The approach to treating Myotonic Dystrophy that is delineated in this grant will be the only approach that treats the root of DM and will provide an avenue for DM therapy that is independent of the specific disease symptoms and has the potential to provide lifelong disease remission. [unreadable] [unreadable] [unreadable]